Article In Brief
Select patients with clinically verified frontotemporal dementia or amyotrophic lateral sclerosis, and pathologic features of both disorders have disease-related expansions in the HTT gene, despite a total absence of standard Huntington’s disease striatal pathology or clinical features. Experts said the findings could have therapeutic implications for drugs in development for Huntington’s disease.
Some patients with clinically confirmed amyotrophic lateral sclerosis or frontotemporal dementia (ALS/FTD), and pathologic features of both diseases, have disease-causing expansions in the HTT gene, despite a complete absence of standard Huntington’s disease (HD) clinical features or striatal pathology, according to a study published November 25th in the journal Neuron.
“We as neurologists tend to put patients into silos based on their clinical presentations,” said lead study author Bryan Traynor, MD, PhD, senior investigator and chief of the neuromuscular diseases research section in the Laboratory of Neurogenetics at the National Institutes of Health (NIH) National Institute of Aging. “What genomics is telling us is that the walls between those silos are much more porous than we previously thought.”
Overlap between the two diseases has been previously reported, Dr. Traynor said, but always in patients with clinical features of both diseases.
While the proportion of affected ALS/FTD patients is small—about one or two out of 1,000—the implications are potentially large since gene-based treatments for HD are currently in clinical trials.
The study was made possible by recent federal funding increases to the NIH for Alzheimer’s disease and related dementias, including the exploration of genomics of non-Alzheimer’s dementing illnesses and by the development of a powerful bioinformatics tool that combs millions of genomic fragments for evidence of expanded repeat sequences.
Study Design, Findings
For the study, Dr. Traynor and colleagues examined whole-genome sequences from 2,442 patients diagnosed with pure ALS/FTD syndromes, 2,599 patients with Lewy body disease (LBD), and 3,158 healthy controls.
The team found pathogenic expanded huntingtin genes in three (0.12 percent) of the ALS/FTD patients and in none of the LBD patients or controls. They then repeated the analysis on a second group, including 3,674 ALS/FTD patients and 31,583 controls, and found five (0.14 percent) expanded huntingtin genes in the patient group and 10 (0.03 percent) in the controls; the difference in carrier rate between the two groups was highly significant. Expansion length in ALS/FTD patients were mainly in the range of 40-45 CAG repeats; expansions of 40 repeats or longer are considered pathogenic. Very low levels of HTT expansion has been previously reported in healthy controls.
To exclude other genetic causes of disease, ALS/FTD patients were tested for pathogenic variants in 50 genes associated with ALS/FTD, Parkinson’s disease, or Alzheimer’s disease. The research team also performed a genome-wide association study on the HTT-positive individuals to look for other potential causes of their disease; none were found.
Post-mortem material was available for two ALS/FTD patients with HTT mutations. In one patient with 40 CAG repeats, who died 11 years after her ALS diagnosis, there was evidence of thinning of the spinal cord anterior roots and loss of motor neurons. Consistent with an ALS diagnosis, anti-TDP-43 staining indicated “rare neurons with nuclear-to-cytoplasmic TDP-43 translocation,” the authors reported. Staining for huntingtin aggregates and p62 showed accumulation of both in the prefrontal cortex, consistent with Huntington’s disease. However, there was no gross or microscopic evidence of neurodegeneration in the striatum, the classic pathologic sign of HD. The investigators observed a roughly similar pattern of neuronal loss and staining in the second patient, with 41 repeats, who died nine years after symptom onset.
“Our data indicate that pathogenic CAG repeat expansions in HTT can give rise to ALS/FTD syndromes that are clinically distinct from the classical Huntington’s disease syndrome,” Dr. Traynor said. “Clinically and pathologically, these patients have ALS/FTD, but at the end of the day, the genomics shows the molecular truth of the matter.”
That HTT mutations can cause symptoms of ALS/FTD “shouldn’t be terribly surprising to us,” he noted, since Huntington’s disease affects the frontal cortex. “So it’s not that much of a stretch” to imagine the same mutation causing a frontal cortex and motor cortex disease that looks like ALS/FTD.
The unanswered question is why there is no striatal degeneration in these patients. The simplest explanation, Dr. Traynor said, is that something unique is protecting the striatum from damage, “but that has to be worked out, which will require more cases.”
As to whether these patients might simply have been unlucky enough to develop two independent fatal neurodegenerative diseases, Dr. Traynor presented a simple statistical argument. Given the known prevalence rates of HD and ALS/FTD, there should be three individuals in the United States, with a population of 327 million, who develop both, assuming nothing else links the two diseases. Instead, the research team found eight cases in a far smaller group. “It is still possible they have both diseases, but it seems extremely unlikely,” he said.
The importance of the study, Dr. Traynor added, is not merely to expand the clinical spectrum of HTT mutations, although that is valuable. But there are currently ongoing trials of antisense oligonucleotides for HD, and if successful, these patients could be considered for those treatments.
“With the advent of gene therapy targeting Huntington’s disease, we can foresee offering a real opportunity for disease modification for these patients. So the message of this paper is, if you are seeing patients in an ALS or FTD clinic, you should screen them for the Huntington’s disease gene. It is a small number of patients, but within that handful, it is potentially going to make a real difference in their lives.”
“This is an extensive study, and so the finding of the HTT expansion in these patients alerts us to the importance of the Huntington’s gene as potentially important in some cases of ALS/FTD,” commented Raymond P. Roos, MD, FAAN, the Marjorie and Robert E. Straus Professor in Neurologic Science in the neurology department at the University of Chicago School of Medicine, who was not involved in the study.
Dr. Roos noted that the two patients at autopsy each died after an unusually long course of the disease at 11 years and nine years. “One interesting avenue of follow-up might be to look for the gene in those with more slowly progressive ALS,” he said. “It may be that cases that involve these HTT mutations are more likely to have atypically long survival.”
“If Huntington’s disease is an expansion of the repeat in the huntingtin locus, then these people have Huntington’s disease, despite not meeting the clinical and pathologic criteria that have been used to describe the disease,” commented Alison Goate, DPhil, a research professor of neurogenetics at the Icahn School of Medicine at Mount Sinai in New York. “This is expanding the clinical symptomatology associated with the CAG repeat expansion in Huntington’s disease.”
(Dr. Goate was not involved in the current study, but noted that her institution provided some of the controls used in the study. She was not alone there; the number of listed contributors tops 400, most of whom were participants of multi-institution, genome-focused consortiums.)
“The most important finding here as far as clinical management is concerned is that we should be screening FTD/ALS patients for expansion in the Huntington’s locus,” she said. “From a mechanistic and therapeutic point of view, we would treat these people in the same way we would treat someone with classical Huntington’s disease.”
Drs. Traynor, Roos, and Goate had no relevant disclosures.